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Open Access Highly Accessed Research article

Spatial distribution of insulin-like growth factor binding protein-2 following hypoxic-ischemic injury

Lauren Fletcher1, Elif Isgor1, Shane Sprague1, Lindsey H Williams2, Betty B Alajajian1, David F Jimenez1 and Murat Digicaylioglu13*

Author Affiliations

1 Department of Neurosurgery, University of Texas Health Science Center at San Antonio, San Antonio, TX 78229, USA

2 School of Medicine, University of Texas Health Science Center at San Antonio, San Antonio, TX 78229, USA

3 Department of Physiology, University of Texas Health Science Center at San Antonio, San Antonio, TX 78229, USA

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BMC Neuroscience 2013, 14:158  doi:10.1186/1471-2202-14-158

Published: 21 December 2013

Abstract

Background

Insulin-like growth factor binding protein-2 (IGFBP-2) regulates the bioavailability, transportation, and localization of insulin-like growth factor-I (IGF-I), an effective neuroprotectant in animal stroke models especially when administered intranasally. Therefore, determining IGFBP-2′s endogenous distribution in the normal and ischemic brain is essential in maximizing the neuroprotective potential of the intranasal IGF-I treatment approach. However, current data on IGFBP-2 is limited to mRNA and in situ hybridization studies. The purpose of this study was to determine if there are any changes in IGFBP-2 protein levels and distribution in ischemic brain and also to determine if IGFBPs play a role in the transportation of intranasally administered IGF-I into the brain.

Results

Using an in vitro approach, we show that ischemia causes changes in the distribution of IGFBP-2 in primary cortical neurons and astrocytes. In addition, we show using the transient middle cerebral artery occlusion (MCAO) model in mice that there is a significant increase in IGFBP-2 levels in the stroke penumbra and core after 72 h. This correlated with an overall increase in IGF-I after stroke, with the highest levels of IGF-I in the stroke core after 72 h. Brain sections from stroke mice indicate that neurons and astrocytes located in the penumbra both have increased expression of IGFBP-2, however, IGFBP-2 was not detected in microglia. We used binding competition studies to show that intranasally administered exogenous IGF-I uptake into the brain is not receptor mediated and is likely facilitated by IGFBPs.

Conclusions

The change in protein levels indicates that IGFBP-2 plays an IGF-I-dependent and -independent role in the brain’s acute (neuroprotection) and chronic (tissue remodeling) response to hypoxic-ischemic injury. Competition studies indicate that IGFBPs may have a role in rapid transportation of exogenous IGF-I from the nasal tissue to the site of injury.

Keywords:
Stroke; Ischemia; Neuroprotection; Insulin-like growth factor binding protein-2; Insulin-like growth factor-I; Intranasal administration